Signature Database

COSMIC_v3.4_SBS_GRCh38

Fitting Method

Sigminer QP

Disease

Colon Adenocarcinoma

Sample

TCGA-CA-6717-01

Description

Primary Tumour

Summary of SBS96
Total number of SBS96 Mutations
12965

Total number of mutations is acceptable

Cosine Similarity

0.986238773

The similarity is great!

Summary: Since both the total number of mutations and cosine similarity of the signature analysis are acceptable, the analysis can be considered useful. Take note of the discrepancies between the reconstructed and observed profiles, if any difference between the models lie within one mutation, then the sample should be flagged

Significant Signatures: ["SBS10a","SBS10b","SBS15","SBS28","SBS37","SBS46"]

Substitution Catalogue, Reconstructed Profiles and Signatures:

The total number of mutations of a certain type ("SBS96", "ID83", "DBS78") can be found in the sample. If the total is too low then the sample may not have significant information to be considered reliable.

The reconstructed model shows the observed profile and the a model based on the significant signatures present in the sample. The cosine similarity ranges from 0 to 1 and is a measure of the likeness of the two plots and determines how well the observed model relates to the reconstruction. A low cosine similarity would mean that the observed plot may not be accurate as a result of a poor sample, few mutations or improper analysis. The discrepancy model also shows the differences between the two plots. If a single mutation has a significant proportion of the discrepancies then the sample analysis may not be reliable. As well as this, the report has a set of signatures that contribute to the sample's substitution profile. If there is a significant proportion of unassigned mutations (over 40%) then the sample provided may either be too small or that the signature may be unknown. Look at the information in the cards to confirm that the signatures are correct based on context, for example a lung cancer sample would most likely contain SBS4 which is associated with tobacco smoking.

Supplementary Details:

The supplementary details section show a box plot which shows significant data for all mutations that were tested for in the sample. The algorithm that was used to estimate the signatures contributing to this sample generated multiple solutions via bootstrapping. Signatures that had a median above a 5% threshold for a significant p-value would be considered as being part of the sample, and those signatures that were below were disregarded.

As well as this, the heatmap provides the Spearman's rank correlation coefficients between signatures across all bootstrapped solutions. This represents the signatures' contributions for the particular sample and how they correlate to each other.

SBS10b -POLE exonuclease domain mutation (30.78%)

Signature SBS10a/SBS10b usually generate large numbers of somatic mutations (>100 mutations per MB) and samples with these signatures have been termed hypermutators

Class: dysfunctional_dna_replication

Subclass: polymerase_mutations

Aetiology: POLE exonuclease domain mutation

Proposed Aetiology Support: Experimental confirmation

Validated in Orthogonal Techniques?: Yes

Signature Version: Mutational Signatures (v3.4 - October 2023)

Identification Study: Alexandrov et al. 2020 Nature

Source: https://cancer.sanger.ac.uk/signatures/sbs/

SBS10a -POLE exonuclease domain mutation (24.18%)

SBS10a/SBS10b usually generate large numbers of somatic mutations (>100 mutations per MB) and samples with these signatures have been termed hypermutators

Class: dysfunctional_dna_replication

Subclass: polymerase_mutations

Aetiology: POLE exonuclease domain mutation

Proposed Aetiology Support: Experimental confirmation

Validated in Orthogonal Techniques?: Yes

Signature Version: Mutational Signatures (v3.4 - October 2023)

Identification Study: Alexandrov et al. 2020 Nature

Source: https://cancer.sanger.ac.uk/signatures/sbs/

SBS28 -POLE exonuclease domain mutation (9.14%)

SBS28 has similarities to SBS17b and these two signatures can be mistaken for one another. Signature SBS28 is found in most samples with SBS10a/SBS10b where it contributes very high numbers of mutations. In contrast, SBS28 contributes much smaller number of mutations in samples lacking SBS10a/SBS10b

Class: dysfunctional_dna_replication

Subclass: polymerase_mutations

Aetiology: POLE exonuclease domain mutation

Proposed Aetiology Support: Experimental studies

Validated in Orthogonal Techniques?: Yes

Signature Version: Mutational Signatures (v3.4 - October 2023)

Identification Study: Alexandrov et al. 2015 Nature Genetics / Nik-Zainal et al. 2016 Nature

Source: https://cancer.sanger.ac.uk/signatures/sbs/

SBS46 -Sequencing artifact (6.81%)

Signature SBS46 was found commonly in colorectal cancers from early releases of TCGA (data released prior 2013)

Class: artefact

Subclass: sequencing_artefact

Aetiology: Sequencing artifact (early releases of TCGA)

Proposed Aetiology Support: Not found in subsequence releases

Validated in Orthogonal Techniques?: Yes

Signature Version: Mutational Signatures (v3.4 - October 2023)

Identification Study: Alexandrov et al. 2020 Nature

Source: https://cancer.sanger.ac.uk/signatures/sbs/

SBS15 -MMR deficiency (5.99%)

SBS15 is one of seven mutational signatures associated with defective DNA mismatch repair and microsatellite instability (MSI) and is often found in the same samples as other MSI associated signatures: SBS6, SBS14, SBS20, SBS21, SBS26, and SBS44

Class: dysfunctional_dna_repair

Subclass: MMR

Aetiology: MMR deficiency

Proposed Aetiology Support: Statistical association; Experimental studies

Validated in Orthogonal Techniques?: Yes

Signature Version: Mutational Signatures (v3.4 - October 2023)

Identification Study: Alexandrov et al. 2013 Nature

Source: https://cancer.sanger.ac.uk/signatures/sbs/

SBS37 -Unknown (5.36%)

NA

Class: unknown

Subclass: unknown

Aetiology: Unknown

Proposed Aetiology Support: Unknown

Validated in Orthogonal Techniques?: Yes

Signature Version: Mutational Signatures (v3.4 - October 2023)

Identification Study: Alexandrov et al. 2020 Nature

Source: https://cancer.sanger.ac.uk/signatures/sbs/

Signature Contribution to Model
Total Number of SBS96 Mutations
12965

Unassigned

2300 (17.74%)

Similar Samples

The pie chart represents all of the cancer sample profiles in Signal's database (broken down by organ) that have a cosine similarity with this sample's profile that is greater than or equal to the given threshold. Lower threshold values are typically less meaningful. Below are the top 5 similar samples compared to the sample.

TCGA-CF-A9FF-01

Disease

Colon Adenocarcinoma

Sample

TCGA-CF-A9FF-01

Description

Primary Tumour

TCGA-A2-A0T5-01

Disease

Mesothelioma

Sample

TCGA-A2-A0T5-01

Description

Primary Tumour

Supplementary Details
Substitution Catalogue
The algorithm that was used to estimate the signatures contributing to this sample generated multiple solutions via bootstrapping. The solution given above corresponds to the median contribution estimate for each signature excluding those whose contribution estimate fell below the sparsity filter threshold (5%) for a significant fraction (p-value) of the solutions (grey boxes). The box plot below provides the contribution estimate distribution for each signature (dashed red line represents sparsity filter threshold).
The heatmap below provides the Spearman's rank correlation coefficients between signatures across all bootstrapped solutions. Clicking on a cell in the heatmap reveals a scatterplot for the given pair of signatures, in which each point represents the signatures' contributions for a particular solution.
The plot compares the contribution for each of the significant signautres in the sample of interest with other samples within the database. The sample of interest is represented by a red dot and you can see the contribution of each signautre in a sample by hovering over any dot.

Technical Details

Technical Details of Signature Analysis Methods
This is where technical details of the mutational signature run will be added ...